Nipah virus is an emerging zoonotic paramyxovirus that has the ability to jump cross species and cause a highly lethal disease in humans. Accordingly, it has been classified as an NIAID category C priority pathogen. We have established that Nipah virus encodes four proteins that inhibit the innate immune or interferon (IFN) response, with three of these proteins acting on the IFN signaling or JAK/STAT pathway. We will determine the precise mechanism(s) of action for the Nipah virus P, V, W and C proteins through characterization of the interaction with STAT1 and identification of additional host cell interacting proteins. We will also investigate a specific role for the W protein in inhibition of the dsRNA-activated toll-like receptor 3 pathway and determine which cellular proteins are involved in this inhibition. The IFN response is the host's primary defense mechanism against viral infection and by inhibiting its induction, Nipah virus may severely impact on the downstream immune responses. Dendritic cells form the interface between the innate and adaptive immune responses and therefore we will examine what effect the expression of the Nipah virus IFN antagonists has on virus-induced dendritic cell maturation and subsequent T cell activation. Finally, we will investigate whether the need for multiple IFN antagonists corresponds to the ability of Nipah virus to replicate in multiple hosts. We will use human, pig, dog and bat cells to determine whether the P, V, W or C proteins display species-specific activity. Our goal is to contribute to the understanding of how viral inhibition of the innate immune response affects virulence.